Mesoporous polymeric particulate material

ABSTRACT

A particulate material comprising porous polymeric particles is described. The porous polymeric particles have an average pore diameter of from 2 to 50 nm and a volume mean particle diameter D[4,3] of less than 100 μm. The material is obtained or obtainable by spray-drying a polymer solution. The particles find use as a solubility-enhancing carrier for active pharmaceutical compounds. Methods of manufacturing the particulate material and pharmaceutical compositions including the particulate material loaded with one or more active pharmaceutical compounds are also described.

RELATED APPLICATION

This application is related to and claims priority from United Kingdompatent application number 1909137.0 filed 25 Jun. 2019, the contents ofwhich are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to a porous particle and particularly,although not exclusively, to a mesoporous particle for use as a carrieror sorbent for drug compounds to enhance the solubility of suchcompounds and/or provide an extended or sustained release pharmaceuticalcomposition.

BACKGROUND

According to US Food and Drug Administration's guidance for industry(2017), drugs can be classified into one of four categories of theBiopharmaceutics Classification System (BCS): high solubility, highpermeability (BCS I); low solubility, high permeability (BCS II); highsolubility, low permeability (BCS III); and low solubility and lowpermeability (BCS IV). A drug substance is considered as “poorly solubledrug” when the highest dose is not soluble in 250 mL of aqueous mediawithin the pH range of 1.0 to 6.8, e.g. 0.1 N HCl or simulated gastricfluid without enzymes; a pH 4.5 buffer; a pH 6.8 buffer or simulatedintestinal fluid without enzymes, at temperature of 37±1° C.

Following oral administration, drugs must dissolve in gastrointestinalfluids in order to be absorbed across the intestinal mucosa into thesystemic circulation and exert a therapeutic action. Formulationdevelopment of low solubility drugs (BCS II and IV) faces greatchallenge as these drugs are poorly absorbed and usually exhibitsubsequent low and variable oral bioavailability (Bosselmann &“Route-Specific Challenges in the Delivery of Poorly Water-SolubleDrugs”, Formulating poorly soluble drugs, 2012, pp. 1-26). Over 40% ofdrugs on the market are in BCS Class II or IV which have low solubility.New chemical entities are even less soluble compared to marketedproducts with a projection of up to 70-90% of drug candidates in thepipeline suffering from low solubility (Ting et al., “Advances inPolymer Design for Enhancing Oral Drug Solubility and Delivery”,Bioconjugate Chem, 2018, 29, pp. 939-952).

The problem of low solubility has so far been addressed usingsolubilisation techniques, including solid dispersion systems, sizereduction, salt formation, use of more highly soluble prodrugs, and theuse of liposomes. Among these techniques, solid dispersion systems arelikely to be increasingly utilised for enhanced solubility of poorlysoluble drugs. Solid dispersion systems are mainly based on a so-called“amorphisation” effect whereby the crystalline drugs are converted intotheir amorphous form when adsorbed onto the solid carrier, whichexhibits superior solubility in comparison with that of the originalcrystalline form. Mesoporous materials (porous materials having anaverage pore diameter of 2 to 50 nm) are considered as highly effectivecarriers for drug amorphisation due to tuneable pore size and highsurface area. Furthermore, this approach is widely applicable forexisting poorly soluble drugs and drug candidates in the pipeline withvarious chemical structures (Ibid. Bosselmann & Williams; Choudhari etal., 2014, “Mesoporous Silica Drug Delivery Systems”, Amorphous SolidDispersions—Theory and Practice, pp. 665-693; Laitinen et al., 2014,“Theoretical Considerations in Developing Amorphous Solid Dispersions”,Amorphous Solid Dispersions—Theory and Practice, pp. 35-90; Riikonen etal., 2018. “Mesoporous systems for poorly soluble drugs—recent trends”,International Journal of Pharmaceutics, 536 (1), 178-186).

The spatial confinement of the drug molecules within the nanometre-scalepores prevents drug recrystallization and maintains the amorphous stateof the drug. As a result of this, a significant enhancement of drugsolubility and subsequent dissolution could be achieved due to theattainment of a highly soluble amorphous form (Garcia-Bennett A.,Feiler, A., 2014, “Mesoporous ASD: Fundamentals”, Amorphous SolidDispersions—Theory and Practice, pp. 637-663; Shen et al., 2017,“Mesoporous materials and technologies for development of oralmedicine”, Nanostructures for Oral Medicine, pp. 699-749).

Current mesoporous materials used for drug delivery purposes are basedon mesoporous silica, discovered at Mobil Corporation (Kresge et al.,1992, “Ordered mesoporous molecular sieves synthesized by aliquid-crystal template mechanism”, Nature, 359, pp. 710-712), andinclude Silsol® and Syloid® marketed by W.R. Grace & Co. The synthesisof mesoporous materials mainly utilises templating agents (pore formingagents) such as surfactant templates, crystal templates, polymerictemplates or emulsion templates to form mesopores in the resulting solidmaterials. Using templating agents to facilitate the pore formation hasbeen proven successful to produce various mesoporous materials such asmesoporous silica and aluminium. However, there is a considerable issueas the process using templating agents is complicated and time-consumingdue to high temperature post-treatment (Nandiyanto & Okuyama, 2011,“Progress in developing spray-drying methods for the production ofcontrolled morphology particles: From the nanometre to submicrometersize ranges”, Advanced Powder Technology, 22, pp. 1-19). For at leastthis reason the current market value of mesoporous silica materials fordrug delivery applications is in the region of thousands of Euros perkg, which greatly increases the cost of the finished dosage form afterdrug loading. Inorganic mesoporous materials such as mesoporous silicaalso suffer from the presence of impurities such as inherent tracemetals and strong alkaline/acidic residues which potentially cause drugstability issues.

Furthermore, although existing mesoporous materials provide increasedsolubility of drug molecules through amorphisation, the corollary isthat the drug is rapidly released from the mesoporous carrier in thebody after the composition has been ingested. Applications are therebylimited to long half-life drugs, or frequent administration is requiredwhen short half-life drugs are incorporated, which leads to problemswith patient compliance.

There is a need for improved drug delivery vehicles which offer enhancedsolubility for poorly soluble drugs and vehicles which may providefurther benefits such as compatibility with short half-life drugs.

The present invention has been devised in the light of the aboveconsiderations.

SUMMARY OF THE INVENTION

At its most general, the present invention relates to porous particlesfor use as a carrier or sorbent for drug compounds.

According to a first aspect of the present invention, there is provideda particulate material comprising porous polymeric particles, theaverage pore diameter being from 2 to 50 nm, wherein the porouspolymeric particles have a volume mean particle diameter D[4,3] of lessthan 100 μm and the material is obtained or obtainable by spray-drying apolymer solution.

In some embodiments, there is provided a particulate material comprisingporous polymeric particles, the porous polymeric particles comprising aplurality of pores having an average pore diameter of from 2 to 50 nm,wherein the porous polymeric particles have a volume mean particlediameter D[4,3] of less than 100 μm and the material is obtained orobtainable by spray-drying a polymer solution.

Porous polymeric particles, more specifically mesoporous polymericparticles comprising pores having an average pore diameter of from 2 to50 nm, are produced by spray drying. The pores are of a size whichfacilitates the adsorption and amorphisation of a wide range of activepharmaceutical compounds (drug compounds), thereby improving thesolubility of the compounds by converting them from a less solublecrystalline phase into a more soluble amorphous phase when adsorbedwithin the pores of the particle.

The invention is therefore particularly applicable to poorly solubledrug compounds, the solubility of which may be enhanced by adsorbing thecompound onto the polymeric particle of the invention. For certain drugcompounds the particulate material may provide around a ten-foldincrease in apparent solubility of the compound loaded onto the particleversus the free compound. The polymeric particles may be produced bystraightforward spray-drying procedures without the need for templatingagents, surfactants or other complex manufacturing or purifyingtechniques, thereby provide a low-cost alternative to existing inorganicmesoporous materials such as mesoporous silica. Additionally thepolymeric particles of the invention, unlike inorganic mesoporousmaterials, do not contain any trace metals or strong alkaline/acidicresidues which would compromise drug stability.

According to a second aspect of the present invention, there is provideda pharmaceutical composition comprising a particulate material accordingto the first aspect loaded with one or more active pharmaceuticalcompounds.

A third aspect of the invention is a pharmaceutical compositionaccording to the second aspect, for use in therapy.

A fourth aspect of the invention is a method of treatment of the humanor animal body, comprising administration of a therapeutically effectiveamount of a pharmaceutical composition according to the second aspect toa patient in need thereof.

A fifth aspect of the invention is a method of manufacturing aparticulate material comprising spray-drying a polymer solution, theparticulate material comprising porous polymeric particles, the averagepore diameter being from 2 to 50 nm, wherein the porous polymericparticles have a volume mean diameter D[4,3] of less than 100 μm.

A sixth aspect of the invention is the use of a particulate materialaccording to the first aspect as a solubility-enhancing carrier for oneor more active pharmaceutical compounds.

According to another aspect of the present invention, there is provideda particulate material comprising porous polymeric particles, theaverage pore diameter being from 2 to 50 nm, wherein the porouspolymeric particles have a volume mean particle diameter D[4,3] of lessthan 100 μm. In some embodiments the material is obtained or obtainableby spray-drying a polymer solution.

As used herein, the term “porous” denotes a particle which contains openpores at the surface of the particle. The particle may also containadditional pores as part of a network of pores through the bulk of theparticle. The term “mesoporous” denotes a particle which containssurface pores having an average pore diameter of from 2 to 50 nm(according to the IUPAC definition).

As used herein, the term “average pore diameter” denotes the meanaverage pore diameter as measured by gas adsorption porosimetry underthe BJH (Barrett-Joyner-Halenda) theory, for example using a pore sizeanalyser such as Quantachrome Nova 4200e, (e.g. according to the methodin ISO 15901-2 of 2006—“Pore size distribution and porosity of solidmaterials by mercury porosimetry and gas adsorption—Part 2: Analysis ofmesopores and macropores by gas adsorption”). The average pore diameterherein is calculated from the total pore volume and specific surfacearea by assuming that pore geometry is cylindrical. The total porevolume may be estimated from the nitrogen amount adsorbed at a relativepressure P/Po of 0.95 by assuming that all the pores are then filledwith liquid nitrogen. The specific surface area may be determined byBrunauer-Emmett-Teller (BET) method (Quantachrome instruments, 2009,Nova operation manual version 11.02).

For example, assuming cylindrical pore geometry, the average porediameter can be expressed as

${{Average}{pore}{size}} = \frac{4V}{S}$

where V is the volume of liquid nitrogen contained in the pores and S isthe specific surface area of porous polymeric particles.

The term “poorly soluble” herein is used generally to encompass theterms “sparingly soluble”, “slightly soluble”, “very slightly soluble”and “practically insoluble”, which are defined in the sectionSolubility—Part III—General Notices of British Pharmacopoeia (BP) 2019and European Pharmacopoeia (EP) 9^(th), as follows:

Sparingly soluble: 30-100 mL of aqueous medium is required to dissolve 1g of substance at a temperature between 15 and 25° C.

Slightly soluble: 100-1000 mL of aqueous medium is required to dissolve1 g of substance at a temperature between 15 and 25° C.

Very slightly soluble: 1000-10,000 mL of aqueous medium is required todissolve 1 g of substance at a temperature between 15 and 25° C.

Practically insoluble: >10,000 mL of aqueous medium is required todissolve 1 g of substance at a temperature between 15 and 25° C.

A first aspect of the invention is a particulate material comprisingporous polymeric particles, more specifically mesoporous polymericparticles.

The porous polymeric particles have a volume mean particle diameter,D[4,3] (also denoted D_(4,3)), of less than 100 μm. In some embodiments,D[4,3] is less than 95 μm, for example less than 90 μm, less than 85 μm,less than 80 μm, less than 75 μm, less than 70 μm, less than 65 μm, lessthan 60 μm, less than 55 μm or less than 50 μm. D[4,3] may be measuredby techniques known to the skilled person, such as laser diffractiontechniques using the method in ISO 13320 of 2009, for example using aMalvern Mastersizer 3000.

In some embodiments, the porous polymeric particles have a D[4,3] of atleast 5 μm, for example at least 10 μm, at least 15 μm, at least 16 μm,at least 17 μm, at least 18 μm, at least 19 μm or at least 20 μm. Insome embodiments, the particle has a D[4,3] of from 5 to 100 μm, forexample from 5 to 90 μm, from 5 to 80 μm, from 10 to 80 μm, from 10 to70 μm, from 15 to 70 μm, from 15 to 60 μm or from 20 to 60 μm.

There are a number of important parameters which can be used to describeporosity properties of porous solids such as specific surface area, porevolume, average pore diameter, and pore size distribution(Recommendations for the Characterization of Porous Solids, Pure & Appl.Chem., Vol. 66, No. 8, pp. 1739-1758, 1994).

The particles of the material have a mean average pore diameter (e.g.average surface pore diameter) of from 2 to 50 nm, as measured by gasadsorption porosimetry under the BJH (Barrett-Joyner-Halenda) theory,for example using a pore size analyser such as Quantachrome Nova 4200e,(e.g. according to the method in ISO 15901-2 of 2006—“Pore sizedistribution and porosity of solid materials by mercury porosimetry andgas adsorption—Part 2: Analysis of mesopores and macropores by gasadsorption”). As explained above, assuming cylindrical pore geometry,the average pore diameter can be expressed as

${{Average}{pore}{size}} = \frac{4V}{S}$

where V is the volume of liquid nitrogen contained in the pores and S isthe specific surface area of porous polymeric particles determinedaccording to the BET theory.

In some embodiments, the average pore diameter is from 2 to 45 nm, forexample from 2 to 40 nm, from 2 to 35 nm, from 2 to 30 nm, from 5 to 45nm, from 5 to 40 nm, from 5 to 35 nm, from 5 to 30 nm, from 10 to 45 nm,from 10 to 40 nm, from 10 to 35 nm or from 10 to 30 nm.

The volume of the pores in the particles of the material (e.g. surfacepore volume) may be greater than 0.10 cm³/g, for example greater than0.15 cm³/g, greater than 0.20 cm³/g, greater than 0.25 cm³/g or greaterthan 0.30 cm³/g. In some embodiments the volume of pores may be from0.10 to 0.50 cm³/g, for example from 0.10 to 0.45 cm³/g, from 0.10 to0.40 cm³/g, from 0.15 to 0.45 cm³/g, from 0.15 to 0.40 cm³/g, from 0.20to 0.45 cm³/g, from 0.20 to 0.40 cm³/g or from 0.25 to 0.40 cm³/g. Porevolume may be measured using the same techniques as used to measureaverage pore diameter, namely gas adsorption porosimetry under the BJH(Barrett-Joyner-Halenda) theory, for example using a pore size analysersuch as Quantachrome Nova 4200e, (e.g. according to the method in ISO15901-2 of 2006—“Pore size distribution and porosity of solid materialsby mercury porosimetry and gas adsorption—Part 2: Analysis of mesoporesand macropores by gas adsorption”).

In some embodiments, the material has a specific surface area greaterthan 10 m²/g, for example greater than 15 m²/g, greater than 20 m²/g,greater than 25 m²/g, greater than 30 m²/g, greater than 35 m²/g orgreater than 40 m²/g. In some embodiments, the material has a specificsurface area of up to 70 m²/g, for example up to 65 m²/g, up to 60 m²/g,up to 55 m²/g or up to 50 m²/g. In some embodiments, the material has aspecific surface area of from 10 to 70 m²/g, for example from 15 to 70m²/g, 15 to 65 m²/g, 15 to 60 m²/g, 20 to 60 m²/g, 20 to 55 m²/g, 25 to55 m²/g, 30 to 55 m²/g, 35 to 60 m²/g, 35 to 55 m²/g or 40 to 50 m²/g.The specific surface area may be measured using the same techniques asused to measure average pore diameter, namely gas adsorption porosimetryunder the BET (Brunauer-Emmett-Teller) theory, for example using a poresize analyser such as Quantachrome Nova 4200e, (e.g. according to themethod in ISO 9277 of 2010).

Pore size distribution is the distribution of pore volume with respectto pore size (IUPAC Compendium of Chemical Terminology, 2014). Mesoporesize calculations are performed using the method of Barrett, Joyner andHalenda (BJH) using the Kelvin model of pore filling starting from theKelvin equation:

${\frac{1}{r_{1}} + \frac{1}{r_{2}}} = {{- \frac{RT}{\sigma^{\lg_{v^{1}}}}}{\ln\left( \frac{p}{p^{0}} \right)}}$

where R is the universal gas constant, T is temperature, r₁ and r₂ arethe principal radii of curvature of the liquid meniscus in the pore,(p/p⁰) is the relative pressure at which condensation occurs, σ^(lg) isthe surface tension of the liquid condensate and v¹ is its molar volume.This approach may be used to determine pore diameter, assuming a modelfor the pore shape in which the pores are cylindrical and the meniscusis hemispherical (r₁=r₂).

Rearrangement of the Kelvin equation and replacement of the principalradii of curvature terms by 2/r_(K) gives:

$r_{K} = \frac{2\sigma^{\lg}v^{1}}{{RT}{\ln\left( \frac{p^{0}}{p} \right)}}$

where r_(K) is often referred to as the Kelvin radius.

If the pore radius of a cylindrical pore is r_(p) and a correction ismade for the thickness of a layer already adsorbed on the pore walls:

r _(p) =r _(K)+2t

So, the pore diameter D is given by:

D=r _(K) +t

The pore size distribution (distribution of pore volume with respect topore size) is usually represented graphically as dV/dD versus D, i.e. aplot of differential pore volume on the y-axis versus pore diameter onthe x-axis. In cases where the variation of particle diameter is large,the y-axis variable may be replaced by dV/d(log D). The unit for dV/dDis (cm³/g)/nm and it represents the pore volume density. For a plot ofdV/dD versus D, the peak area under the curve between any two pore sizesis proportional to the partial specific pore volume for the specificpore size interval.

Determination of pore volume, pore diameter and pore size distributionunder the BJH theory may be made according to the method in ISO 15901-2of 2006—“Pore size distribution and porosity of solid materials bymercury porosimetry and gas adsorption—Part 2: Analysis of mesopores andmacropores by gas adsorption”.

In some embodiments, the material has a pore size distribution of from0.5 to 100 nm, for example from 0.5 to 95 nm, from 0.5 to 90 nm, from0.5 to 85 nm, from 0.5 to 80 nm, from 1 to 100 nm, from 1 to 95 nm, from1 to 90 nm, from 1 to 85 nm, from 1 to 80 nm, from 1 to 75 nm, from 1 to70 nm, from 2 to 100 nm, from 2 to 95 nm, from 2 to 90 nm, from 2 to 85nm, from 2 to 80 nm, from 2 to 75 nm or from 2 to 70 nm. That is to say,the pores may have diameters falling within one of the above ranges.

The properties of the pores of the particle described herein, such aspore volume, average pore diameter and pore size distribution relate tosurface pores (i.e. open pores at the surface of the particles withinthe material). The particles may nevertheless also contain internal(closed or open) pores formed during the spray-drying process, but theskilled person will understand that such internal closed pores cannot bemeasured using surface analysis techniques such as BET or BJH analysis.

In some embodiments, the porous polymeric particles comprise bothinternal and external pores, which may be confirmed for example byevaluation of SEM images. Without wishing to be bound by theory, it isbelieved that external (surface) pores act as a gateway for drug speciesto pass through and migrate into the interior of the particles during adrug-loading process, and to facilitate release of the drug from theparticle upon contact with biological fluid. It is also believed thatthe presence of an internal mesoporous network enhances the“amorphisation” effect wherein crystalline drug compounds are convertedinto their high-energy amorphous form which exhibits superior solubilityin comparison with the lower energy crystalline form.

The particles are polymeric particles, i.e. particles which comprise orconsist of one or more polymeric materials. In some embodiments, theparticles comprise or consist of one or more biocompatible polymericmaterials, that is to say polymeric materials which have been approvedfor medical applications. In some embodiments, the particles comprise orconsist of one or more cellulosic polymers. A cellulosic polymer is apolymer which is a derivative of cellulose, for example a polymerobtained by the chemical modification of the side chains of cellulose.In some embodiments the cellulosic polymer is selected from one or moreof cellulose esters and cellulose ethers. In some embodiments, thecellulosic polymer is selected from one or more of cellulose acetatebutyrate, cellulose acetate, methyl cellulose, ethyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl celluloseand hydroxypropyl methyl cellulose. In some embodiments, the cellulosicpolymer is selected from one or more of cellulose acetate butyrate,cellulose acetate, ethyl cellulose and hydroxypropyl cellulose. In someembodiments, the particles comprise or consist of cellulose acetatebutyrate. In some embodiments, the particles comprise or consist ofethyl cellulose. Cellulosic polymers are preferred due to theirbiocompatibility, which makes them safe for in vivo administration, andhigh glass transition temperature, which facilitates pore formation.

In some embodiments, the particles comprise a single type of polymer. Insome embodiments, the particles comprise a single type of polymer andthe polymer is a derivative of cellulose. In some embodiments, theparticles comprise a single type of polymer and the polymer is selectedfrom cellulose esters and cellulose ethers. In some embodiments, theparticles comprise a single type of polymer and the polymer is selectedfrom cellulose acetate butyrate, cellulose acetate, methyl cellulose,ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,carboxymethyl cellulose and hydroxypropyl methyl cellulose. In someembodiments, the particles comprise a single type of polymer and thepolymer is selected from cellulose acetate butyrate, cellulose acetate,ethyl cellulose and hydroxypropyl cellulose.

In other embodiments, the particles comprise two or more different typesof polymer. In some embodiments, the particles comprise two differenttypes of polymer. In some embodiments, the particles comprise two ormore different types of polymer which are each independently selectedfrom derivatives of cellulose. In some embodiments, the particlescomprise two or more different types of polymer which are eachindependently selected from cellulose esters and cellulose ethers. Insome embodiments, the particles comprise two or more different types ofpolymer which are each independently selected from cellulose acetatebutyrate, cellulose acetate, methyl cellulose, ethyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl celluloseand hydroxypropyl methyl cellulose. In some embodiments, the particlescomprise two or more different types of polymer which are eachindependently selected from cellulose acetate butyrate, celluloseacetate, ethyl cellulose and hydroxypropyl cellulose. In someembodiments, the particles comprise two different types of polymerwherein a first polymer is ethyl cellulose and a second polymer iscellulose acetate butyrate.

Including two or more different types of polymer in the solution to bespray-dried and thereby in the final polymeric particles allows theproperties of the particles, such as pore morphology, to be tailored byvarying the relative quantities of the two or more polymers.

As will be understood by the skilled person, the polymer in the solutionwhich is spray-dried to create the porous particles will be the samepolymer which forms the porous particles themselves, so any discussionherein of the nature of the polymer in the particles applies equally tothe polymer in the solution, and vice versa.

In some embodiments, the particles comprise or consist of celluloseacetate butyrate having a butyryl content of from 15 to 50 wt %, anacetyl content of from 1 to 30 wt % and a hydroxyl content of from 0.5to 5 wt %. Suitable cellulose acetate butyrate polymers are known to theskilled person and commercially available, for example from EastmanChemical.

In some embodiments, the polymer has a glass transition temperature(T_(g)) of at least 60° C., or greater than 60° C. In some embodiments,the polymer has a glass transition temperature of at least 65° C., forexample at least 70° C., at least 75° C., at least 80° C., at least 85°C., at least 90° C., at least 95° C. or at least 100° C., for examplegreater than 100° C. In some embodiments, the polymer has a glasstransition temperature of from 60 to 200° C., for example from 65 to200° C., 70 to 200° C., 75 to 200° C., 80 to 200° C., 85 to 200° C., 90to 200° C., 100 to 200° C., 100 to 195° C., 100 to 190° C., 100 to 185°C., 100 to 180° C., 100 to 175° C., 100 to 170° C. or 100 to 165° C.Such glass transition temperatures are preferred because they providethermally stable polymers which can endure high temperature and allowthe diffusion of solvents out of the polymer during spray drying withoutmodifying the internal pore structure.

In some embodiments, the inlet temperature during spray-drying is lowerthan the glass transition temperature T_(g) of the polymer in thepolymer solution. In this way, pore formation is facilitated and theformation of mesopores of the correct size is promoted. A polymer with aT_(g) higher than the inlet temperature has good thermal stability andcan endure high temperature and allow the diffusion of solvents out ofthe polymer without modifying the internal pore structure. In someembodiments, the polymer has a glass transition temperature (T_(g)) ofat least 100° C., or greater than 100° C., since this provides for amore flexible spray-dryer inlet temperature while ensuring that theinlet temperature remains below T_(g) of the polymer (i.e. the inlettemperature of the spray-dryer may be at least up to 100° C.).

In some embodiments, the weight average molecular weight (M_(w)) of thepolymer is from 10,000 to 1,000,000 g/mol, for example from 20,000 to900,000 g/mol, from 25,000 to 800,000 g/mol, from 30,000 to 700,000g/mol, from 40,000 to 600,000 g/mol or from 50,000 to 500,000 g/mol.

In some embodiments, the number average molecular weight (M_(n)) of thepolymer is from 5,000 to 500,000 g/mol, for example from 6,000 to450,000 g/mol, from 7,000 to 400,000 g/mol, from 8,000 to 300,000 g/mol,from 9,000 to 200,000 g/mol or from 10,000 to 100,000 g/mol.

In some embodiments, the polymer is ethyl cellulose with an M_(w) offrom 90,000 to 450,000.

In some embodiments, the polymer is cellulose acetate with an M_(n) offrom 30,000 to 40,000.

In some embodiments, the polymer is cellulose acetate butyrate with anM_(n) of from 30,000 to 70,000.

In some embodiments, the polymer is a cellulose derivative polymer andhas a viscosity of from 0.35 to 120 cps as measured by ASTM D1343(Standard Test Method for Viscosity of Cellulose Derivatives byBall-Drop).

In some embodiments, the polymer is a cellulose derivative polymer andhas a viscosity of from 0.35 to 120 cps as measured by ASTM D1343(Standard Test Method for Viscosity of Cellulose Derivatives byBall-Drop) and a glass transition temperature of at least 60° C.

In some embodiments, the polymer is a cellulose derivative polymer andhas a viscosity of from 0.35 to 120 cps as measured by ASTM D1343(Standard Test Method for Viscosity of Cellulose Derivatives byBall-Drop), and the inlet temperature during spray-drying is lower thanthe glass transition temperature T_(g) of the polymer.

Another aspect of the invention is a pharmaceutical compositioncomprising a particulate material according to the first aspect and oneor more active pharmaceutical compounds. In some embodiments, one ormore active pharmaceutical compounds are adsorbed onto the surface ofthe particles, including within the surface pores. In some embodiments,one or more active pharmaceutical compounds are contained within theinternal structure of the particle, for example within an internal pore,by providing a solution for spray-drying which contains both the polymerand the one or more active pharmaceutical compounds. This may provide apharmaceutical composition which provides extended (or sustained)release of the one or more active pharmaceutical compounds in vivo afteringestion of the composition, since the one or more activepharmaceutical compounds are at least partially entrapped within thestructure of the particle which prevents immediate release.

Because the surface pores of the particles have an average pore diameterof from 2 to 50 nm, the one or more active pharmaceutical compoundsadsorbed to the surface of the particles within the pores are in anamorphous phase (i.e. they are amorphised), increasing the solubility ofthe one or more active pharmaceutical compounds. The material of theinvention thereby provides a means to enhance the solubility of activepharmaceutical compounds, for example enhancing the solubility of poorlysoluble active pharmaceutical compounds.

In some embodiments, the active pharmaceutical compounds are locatedonly within the surface pores, i.e. not within the internal structure ofthe particle, which may be achieved by post-loading the particles withactive pharmaceutical compounds after spray-drying a polymer solution.For example, the particles may be immersed in a solution or suspensionof one or more active pharmaceutical compounds.

In some embodiments, the one or more active pharmaceutical compounds inthe pharmaceutical composition are selected from one or more poorlysoluble active pharmaceutical compounds as defined herein. Thesolubility of such compounds is increased by their loading onto themesoporous particles produced during spray drying.

In some embodiments, the one or more active pharmaceutical compounds areselected from molecular species having a molecular weight of from 100g/mol to 1000 g/mol, for example from 100 g/mol to 900 g/mol, from 100g/mol to 800 g/mol, from 100 g/mol to 700 g/mol, from 100 g/mol to 600g/mol, from 100 g/mol to 500 g/mol, from 150 g/mol to 450 g/mol, from150 g/mol to 400 g/mol or from 200 g/mol to 400 g/mol.

Non-limiting examples of compounds which may be present in thecomposition include cardiovascular drugs such as Felodipine,Telmisartan, Valsartan, Carvedilol, Nifedipine, Nimodipine andCaptopril; lipid-lowering drugs such as Lovastatin, Fenofibrate andEzetimibe; antiviral drugs such as Atazanavir and Ritonavir; analgesicssuch as Ibuprofen, Meloxicam, Ketoprofen, Aceclofenac, Celecoxib,Indomethacin, Phenylbutazone and Flurbiprofen; anti-fungal drugs such asItraconazole, Griseofulvin and Ketoconazole; antiepileptic drugs such asCarbamazepine, Oxcarbazepine and Rufinamide; anticancer drugs such asCamptothecin, Danazol and Paclitaxel; and other poorly soluble drugssuch as Glibenclamide, Cyclosporine, Cinnarizine, Furosemide andDiazepam. One or a combination of two or more of these compounds may bepresent. In some embodiments, the one or more active pharmaceuticalcompounds are selected from one or more of Furosemide, Ibuprofen andFelodipine.

In some embodiments, the pharmaceutical composition consists of aparticulate material according to the first aspect and one or moreactive pharmaceutical compounds. In other words, the composition maycontain only a particulate material according to the first aspect andone or more active pharmaceutical compounds. This may ensure that noadditional additives are present which may interfere with theamorphisation or activity of the active pharmaceutical compounds.

The pharmaceutical composition may be in powder form comprising a powdercomprising a particulate material according to the first aspect. Such apowdered pharmaceutical composition offers a useful intermediate in thepreparation of pharmaceutical dosage forms, for example tablets (whichmay be prepared by tabletting processes) or hard capsules (which may beprepared by capsule-filling processes).

The pharmaceutical composition may comprise the one or more activepharmaceutical compounds at a drug loading of from 1% w/w to 40% w/w,for example from 1% w/w to 30% w/w, from 2% w/w to 40% w/w, from 2% w/wto 35% w/w, from 2% w/w to 30% w/w, from 2% w/w to 29% w/w, from 2% w/wto 28% w/w, from 2% w/w to 27% w/w, from 2% w/w to 26% w/w, from 2% w/wto 25% w/w, from 5% w/w to 40% w/w, from 5% w/w to 35% w/w, from 5% w/wto 30% w/w, from 5% w/w to 25% w/w, from 10% w/w to 30% w/w, from 10%w/w to 25% w/w or from 15 wt % to 25 wt %. Herein, “% w/w” refers to theamount of compound with respect to the amount of particulate materialalone. For example, a composition comprising 5 g of activepharmaceutical compound loaded onto 100 g of polymeric particles (to atotal composition mass of 105 g) would have a drug loading of 5% w/w.

The particulate material of the invention is obtained or obtainable byspray-drying a polymer solution. In some embodiments, the particulatematerial of the invention is obtained by spray-drying a polymersolution.

Options and preferences for the polymer or polymers within the solutionare as set out above in the context of the polymer or polymers making upthe polymeric particles. So, for example, the polymer solution maycomprise a cellulosic polymer.

The solution comprises a solvent and one or more polymers. The solventmay be a single solvent or a solvent mixture. In some embodiments, thesolvent is a solvent mixture. In some embodiments, the solvent is amixture of a polar protic solvent and a polar aprotic solvent. In someembodiments, the solvent is a mixture of water and an organic solvent,for example a polar organic solvent.

In some embodiments, the solvent is a mixture of a first solvent and asecond solvent, wherein the first solvent is a solvent in which the oneor more polymers is soluble and the second solvent is a solvent in whichthe one or more polymers is poorly soluble or insoluble, wherein“soluble” indicates that at least 1 g of the one or more polymers issoluble in 10 mL of solvent at 25° C., “poorly soluble” indicates thatless than 1 g of the one or more polymers is soluble in 10 mL of solventat 25° C. and “insoluble” indicates that very little or no amount of theone or more polymers is soluble in 10 mL of solvent at 25° C. It hasbeen found that such a mixture of a first solvent in which the one ormore polymers is soluble and a second solvent in which the one or morepolymers is poorly soluble provides particularly good pore morphology inthe spray-dried mesoporous polymeric particles, offering furtherimprovement in the amorphisation and solubility of adsorbed compounds.

In some embodiments, the solvent mixture comprises at least 10% v/v ofthe first solvent and at least 5% v/v of the second solvent. In someembodiments, the solvent mixture comprises at least 20% v/v of the firstsolvent and at least 5% v/v of the second solvent. In some embodiments,the solvent mixture comprises at least 50% v/v of the first solvent andat least 5% v/v of the second solvent. In some embodiments, the solventmixture comprises at least 60% v/v of the first solvent and at least 5%v/v of the second solvent. In some embodiments, the solvent mixturecomprises at least 60% v/v of the first solvent and at least 5% v/v ofthe second solvent. In some embodiments, the solvent mixture comprisesat least 80% v/v of the first solvent and at least 5% v/v of the secondsolvent.

In some embodiments, the solvent mixture comprises 75 to 95% v/v of thefirst solvent and 5 to 25% v/v of the second solvent, for example 80 to90% v/v of the first solvent and 10 to 20% v/v of the second solvent.

In some embodiments, the solvent mixture consists of the first andsecond solvents. In some embodiments, the solvent mixture consists of atleast 80% v/v of the first solvent and at least 10% v/v of the secondsolvent. In some embodiments, the solvent mixture consists of around 80%v/v of the first solvent and around 20% v/v of the second solvent. Insome embodiments, the solvent mixture consists of 75 to 95% v/v of thefirst solvent and 5 to 25% v/v of the second solvent, for example 80 to90% v/v of the first solvent and 10 to 20% v/v of the second solvent.

In some embodiments, the first solvent is acetone and the second solventis water. In some embodiments, the first solvent is ethyl acetate andthe second solvent is isopropanol.

In some embodiments, the solvent comprises a polar aprotic solvent (suchas acetone) in an amount of greater than 50% v/v, for example at least55% v/v, at least 60% v/v, at least 65% v/v, at least 70% v/v, at least75% v/v or at least 80% v/v, with the balance being a polar proticsolvent (such as water).

In some embodiments the solvent mixture comprises or consists of waterand acetone. This particular mixture of solvents has been found toprovide particularly good pore morphology in the spray-dried polymericparticles.

In some embodiments, the solvent mixture comprises or consists ofacetone and water in a ratio of 80:20, 85:15 or 90:10 by volume.

The solution may be prepared by dissolving the one or more polymers inthe solvent or solvent mixture. In some embodiments, the solutioncomprises at least 1% (w/v) polymer, for example at least 1.5% (w/v)polymer, at least 2% (w/v) polymer or at least 2.5% (w/v) polymer. Insome embodiments, the balance of the solution is the solvent. In someembodiments, the solution comprises from 1% (w/v) to 20% (w/v) polymer,for example from 1.1% (w/v) to 18% (w/v) polymer, from 1.2% (w/v) to 15%(w/v) polymer, from 1.3% (w/v) to 12% (w/v) polymer, from 1.4% (w/v) to10% (w/v) polymer, from 1.5% (w/v) to 10% (w/v) polymer, from 1.6% (w/v)to 8% (w/v) polymer, from 1.7% (w/v) to 6% (w/v) polymer, from 1.8%(w/v) to 5% (w/v) polymer or from 1.9% (w/v) to 3% (w/v) polymer. Insome embodiments, the solution comprises around 2% (w/v) polymer. Itwill be understood that “% (w/v)” represents the weight of polymer ingrams added to 100 mL of solvent. So, for example, when 4 g of polymeris added to 200 mL solvent to provide a solution, the solution contains2% (w/v) polymer.

In some embodiments, the solution is free from any additives ortemplating agents. In some embodiments, the solution consists of thesolvent and dissolved polymer. Templating agents (also called“pore-forming agents”) are traditionally used as a way to create porousmaterials. However in the present invention the porous polymericparticles form without the need for templating agents. This ensures thatthe final product is free of any contamination by templating agentswhich may affect the pharmaceutical acceptability of the product orinterfere with the adsorption or solubility of drug compounds.

The polymer solution may be prepared by adding the one or more polymersto the solvent or solvent mixture and performing gentle mixing to effectdissolution and homogeneity. In some embodiments, the mixing isperformed in a covered chamber to minimise solvent loss by evaporation.In some embodiments, mixing is performed with a magnetic stirred with amixing speed of up to 500 rpm, for example up to 450 rpm, up to 400 rpm,up to 350 rpm, up to 300 rpm or up to 250 rpm. In some embodiments,mixing is performed at a temperature of from 10° C. to 30° C., forexample from 12° C. to 28° C., from 15° C. to 25° C. or from 18° C. to22° C. In some embodiments, mixing is performed for a period of from 15to 120 mins, for example from 20 to 100 mins, from 25 to 90 mins or from30 to 60 mins.

The polymer solution may be spray dried in the absence of any activepharmaceutical compounds to produce the mesoporous polymeric particleswhich are then subsequently contacted with one or more activepharmaceutical compounds to adsorb the compound onto the particlesurface. However in other embodiments, in addition to the polymer, thepolymer solution comprises one or more active pharmaceutical compounds.The solution containing both polymer and one or more activepharmaceutical compounds is then spray-dried to produce mesoporousparticles pre-loaded with one or more active pharmaceutical compounds.

Such addition of one or more active pharmaceutical compounds to thepolymer solution may be preferred when an extended or sustained releasepharmaceutical composition is desired. The particles produced by suchmethods contain the active pharmaceutical compound not only adsorbed atthe surface, but embedded within the particle, for example intimatelydispersed within the particle polymer matrix or adsorbed to the surfaceof internal pores. The release of such active pharmaceutical compoundfrom the particles in vivo is hindered, thereby providing an extended orsustained release composition in which active pharmaceutical compound isreleased more slowly over an extended period of time.

Without wishing to be bound by theory, it is believed that when polymerand active pharmaceutical compound are “co-spray dried” (i.e. bothpolymer and active pharmaceutical compound are present in the solutionto be spray dried), the spray dried porous polymeric particles contain agreater amount of active pharmaceutical compound which is contained bothwithin the internal structure of the particle and within pores at thesurface of the particle. This is an alternative to “post-loading”techniques in which only the polymer is spray-dried and the spray driedparticles are later contacted with active pharmaceutical compound toeffect loading of the active pharmaceutical compound into the surfacepores of the particle.

In some embodiments, the amount of the one or more active pharmaceuticalcompounds present in the polymer solution (i.e. the drug loading of thepolymer solution) is from 1% w/w to 40% w/w, for example from 1% w/w to30% w/w, from 2% w/w to 40% w/w, from 2% w/w to 35% w/w, from 2% w/w to30% w/w, from 2% w/w to 29% w/w, from 2% w/w to 28% w/w, from 2% w/w to27% w/w, from 2% w/w to 26% w/w, from 2% w/w to 25% w/w, from 5% w/w to40% w/w, from 5% w/w to 35% w/w, from 5% w/w to 30% w/w, from 5% w/w to25% w/w, from 10% w/w to 30% w/w, from 10% w/w to 25% w/w or from 15 wt% to 25 wt %, wherein “% w/w” refers to the amount of one or more activepharmaceutical compounds with respect to the amount of polymer alone.For example, a polymer solution comprising 5 g of active pharmaceuticalcompound and 100 g of polymer (to a total mass of 105 g) would have adrug loading of 5% w/w.

In some embodiments, the one or more active pharmaceutical compounds inthe solution are selected from one or more poorly soluble activepharmaceutical compounds. The solubility of such compounds is increasedby their loading onto the mesoporous particles produced during spraydrying.

In some embodiments, the one or more active pharmaceutical compounds areselected from molecular species having a molecular weight of from 100g/mol to 1000 g/mol, for example from 100 g/mol to 900 g/mol, from 100g/mol to 800 g/mol, from 100 g/mol to 700 g/mol, from 100 g/mol to 600g/mol, from 100 g/mol to 500 g/mol, from 150 g/mol to 450 g/mol, from150 g/mol to 400 g/mol or from 200 g/mol to 400 g/mol.

Non-limiting examples of compounds which may be added to the solutioninclude cardiovascular drugs such as Felodipine, Telmisartan, Valsartan,Carvedilol, Nifedipine, Nimodipine and Captopril; lipid-lowering drugssuch as Lovastatin, Fenofibrate and Ezetimibe; antiviral drugs such asAtazanavir and Ritonavir; analgesics such as Ibuprofen, Meloxicam,Ketoprofen, Aceclofenac, Celecoxib, Indomethacin, Phenylbutazone andFlurbiprofen; anti-fungal drugs such as Itraconazole, Griseofulvin andKetoconazole; antiepileptic drugs such as Carbamazepine, Oxcarbazepineand Rufinamide; anticancer drugs such as Camptothecin, Danazol andPaclitaxel; and other poorly soluble drugs such as Glibenclamide,Cyclosporine, Cinnarizine, Furosemide and Diazepam. One or a combinationof two or more of these compounds may be dissolved in the polymersolution. In some embodiments, the one or more active pharmaceuticalcompounds are selected from one or more of Furosemide, Ibuprofen andFelodipine.

Another aspect of the invention is a method of manufacturing aparticulate material comprising spray-drying a polymer solution, theparticulate material comprising porous polymeric particles, the averagepore diameter being from 2 to 50 nm, wherein the porous polymericparticles have a volume mean diameter D[4,3] of less than 100 μm.

In the method of manufacturing a particulate material, the polymer,polymer solution and the particulate material itself are as discussedabove in the context of the first aspect.

In some embodiments, the method comprises a preliminary step ofpreparing a polymer solution, comprising dissolving one or more polymersin a solvent. The solvent and one or more polymers may be as describedabove in relation to the first aspect. For example, the solvent may bean acetone:water mixture and the polymer may be a cellulosic polymer.The preliminary step may also include dissolving one or more activepharmaceutical compounds in the solvent along with the polymer. In otherembodiments the preparation of the polymer solution comprises the mixingof only the polymer and the solvent, i.e. the solution contains onlypolymer and solvent and no further additives or excipients.

To form the porous polymeric particles, the above-described polymersolution is subjected to a spray-drying process. Such processes arewell-known to the skilled person.

Any suitable spray-drying apparatus may be used in the method of theinvention.

In some embodiments, the inlet temperature is from 60 to 175° C., forexample from 60 to 170° C., 60 to 165° C., 60 to 160° C., 60 to 155° C.,60 to 150° C., 60 to 145° C. or 60 to 140° C. In some embodiments, theinlet temperature is about 100° C.

In some embodiments, the inlet temperature during spray-drying of thepolymer solution is lower than the glass transition temperature T_(g) ofthe polymer in the polymer solution. So, for example, if the glasstransition temperature of the polymer is 130° C., the inlet temperatureduring spray-drying may be less than 130° C. In this way, pore formationis facilitated and the formation of mesopores of the correct size ispromoted.

The spray-dryer may be operated in closed mode. The spray-dryer mayutilise an inert carrier gas, for example nitrogen or carbon dioxide. Anatomisation pressure of from 100 to 500 kPa may be used duringspray-drying, for example from 100 to 450 kPa, 100 to 400 kPa, 100 to350 kPa, 100 to 300 kPa, 150 to 250 kPa or about 200 kPa.

In some embodiments, the spray-drying is carried out in a spray-dryerunder closed-mode with nitrogen, an inlet temperature of from 60 to 180°C. and an atomisation pressure of from 100 to 500 kPa.

Suitable spray-drying apparatus which may be used in the presentinvention includes the mini spray dryer Buchi B-290 with the Inert LoopBuchi B-295 (Flawil, Switzerland).

The particular flow rates used during spray drying will depend on thechoice of spray dryer and the scale of manufacture. For theabove-mentioned mini spray dryer Buchi B-290 with the Inert Loop BuchiB-295, a feed flow rate (flow rate of the polymer solution) of from 1mL/min to 10 mL/min may be used during the spray drying process, forexample from 2 mL/min to 8 mL/min, from 3 mL/min to 6 mL/min or about 5mL/min. An inert gas flow rate of from 200 L/hour to 1000 L/hour may beused during the spray drying process, for example from 250 L/hour to1000 L/hour, 400 L/hour to 800 L/hour or about 600 L/hour. In someembodiments, the inert gas is nitrogen. A drying gas flow rate of from10 m³/hour to 50 m³/hour may be used during the spray drying process,for example from 15 m³/hour to 45 m³/hour, 20 m³/hour to 40 m³/hour, 24m³/hour to 35 m³/hour or about 30 m³/hour.

The choice of spray drying apparatus is not particularly limited and thespray dryer may be chosen based on e.g. the scale of manufacturerequired. For pilot scale manufacture a larger spray dryer may beemployed, for example the Niro Mobile Minor spray dryer. The skilledperson will understand that the above mentioned feed flow rate, inertgas (atomisation) flow rate and drying gas flow rate will changeaccordingly based on the size of the spray dryer and the skilled personis able to choose suitable flow rates.

For example, for the Niro Mobile Minor spray dryer the feed flow rate(flow rate of the polymer solution) may be from 1.0 kg/hour to 6.0kg/hour, the inert gas (atomisation) flow rate may be from 4 kg/hour to25 kg/hour and the drying gas flow rate may be from 10 kg/hour to 80kg/hour.

The outlet temperature during spray drying is a function of variousprocess parameters such as inlet temperature, feed rate and flow rate,but generally may be within the range 40 to 120° C.

In some embodiments, the method comprises one or more processing stepsperformed on the particulate material after spray-drying. For example,the material may be subjected to one or more drying steps to remove anyresidual solvent.

In some embodiments, the method comprises a step of contacting thespray-dried particulate material with one or more active pharmaceuticalcompounds. In some embodiments, the method comprises a step ofcontacting the spray-dried particulate material with a solution of oneor more active pharmaceutical compounds (“drug solution”). This may beachieved by dissolving the one or more active pharmaceutical compoundsin a suitable solvent and combining the solution with the particulatematerial to create a suspension. In this way, the active pharmaceuticalcompound becomes loaded onto the surface of the particles, i.e. adsorbedonto the surface, including within the mesopores. The suspension may bestirred to improve loading efficiency. In some embodiments, the solventin which the one or more active pharmaceutical compounds are dissolvedis an alcohol. In some embodiments, the solvent is ethanol.

In some embodiments, the amount of the one or more active pharmaceuticalcompounds in the drug solution is at least 2 mg/mL, for example at least2.5 mg/mL, at least 3 mg/mL, at least 3.5 mg/mL, at least 4 mg/mL, atleast 4.5 mg/mL or at least 5 mg/mL. In some embodiments, the amount ofthe one or more active pharmaceutical compounds in the drug solution isup to 50 mg/mL, for example up to 45 mg/mL, up to 40 mg/mL, up to 35mg/mL, up to 30 mg/mL, up to 25 mg/mL or up to 20 mg/mL. In someembodiments, the amount of the one or more active pharmaceuticalcompounds in the drug solution is from 2 to 50 mg/mL, for example from 2to 40 mg/mL, from 2 to 30 mg/mL, from 5 to 20 mg/mL, from 5 to 15 mg/mLor about 10 mg/mL.

In some embodiments, the drug loading in the drug solution is from 1%w/w to 40% w/w, for example from 1% w/w to 30% w/w, from 2% w/w to 40%w/w, from 2% w/w to 35% w/w, from 2% w/w to 30% w/w, from 2% w/w to 29%w/w, from 2% w/w to 28% w/w, from 2% w/w to 27% w/w, from 2% w/w to 26%w/w, from 2% w/w to 25% w/w, from 5% w/w to 40% w/w, from 5% w/w to 35%w/w, from 5% w/w to 30% w/w, from 5% w/w to 25% w/w, from 10% w/w to 30%w/w, from 10% w/w to 25% w/w or from 15 wt % to 25 wt %, wherein “% w/w”refers to the amount of one or more active pharmaceutical compounds withrespect to the amount of particulate material alone added to the drugsolution. For example, a drug solution comprising 5 g of activepharmaceutical compound and 100 g of polymeric particles (to a totalmass of 105 g) would have a drug loading of 5% w/w.

In some embodiments the solution contains one active pharmaceuticalcompound.

In some embodiments the suspension of the particles in the drug solutionis agitated, or stirred. This promotes the uptake of activepharmaceutical compound by the particles in the suspension.

The suspension may be left for a period of at least an hour, for exampleat least 2 hours, at least 5 hours or at least 10 hours, optionally withstirring. The suspension may be left for a period of up to 20 hours, forexample up to 18 hours, up to 15 hours or up to 12 hours, optionallywith stirring.

After the suspension has been left for a suitable amount of time toprovide the desired drug loading, the drug-loaded particulate materialmay be separated from the suspension, for example by filtration orspray-drying. In some embodiments, the suspension of porous particles inthe drug solution is spray-dried. The conditions for spray-drying may beas set out above in the context of the spray-drying of the polymersolution. In some embodiments, after filtration or spray drying, thematerial is subjected to a further drying step, for example in an ovenor other high ambient temperature environment.

In some embodiments, drying of the drug-loaded particulate material iscarried out until the residual solvent content of the material is lessthan or equal to 0.5 wt % based on the total weight of particulatematerial, solvent and active pharmaceutical compound, for example lessthan or equal to 0.4 wt %, less than or equal to 0.3 wt % or less thanor equal to 0.2 wt %. This can be achieved for example by providing alonger residence time in the spray-dryer, or by performing an additionaldrying step for a sufficient period of time.

Alternative methods of loading active pharmaceutical onto theparticulate material may be used, for example solvent-free methods.These have the advantage that no subsequent drying step to removesolvent is required. However, in general solvent-based methods arepreferred because a higher drug loading efficiency is possible.

As explained above, the porous particulate material of the invention maybe loaded with one or more active pharmaceutical compounds. In someembodiments, the surface of the porous particulate material is loadedwith one or more active pharmaceutical compounds. In some embodiments,the porous particulate material is loaded with one active pharmaceuticalcompound (i.e. a single type/species of compound).

The active pharmaceutical compound or compounds which may be loaded ontothe material of the invention is not particularly limited. It may beparticularly useful to load one or more compounds of poor solubilityonto the material, since adsorption into the mesopores of the materialmay increase the solubility, thereby improving the usefulness of thecompound.

In some embodiments, the one or more active pharmaceutical compounds areeach independently selected from compounds in BCS Class II or BCS ClassIV according to the US Food and Drug Administration's guidance. In someembodiments, the one or more active pharmaceutical compounds are eachindependently selected from compounds which are sparingly soluble,slightly soluble, very slightly soluble or practically insoluble asdefined in Solubility—Part III— General Notices of British Pharmacopoeia(BP) 2019 and European Pharmacopoeia (EP) 9th Edition.

In some embodiments, the one or more active pharmaceutical compounds areselected from molecular species having a molecular weight of from 100g/mol to 1000 g/mol, for example from 100 g/mol to 900 g/mol, from 100g/mol to 800 g/mol, from 100 g/mol to 700 g/mol, from 100 g/mol to 600g/mol, from 100 g/mol to 500 g/mol, from 150 g/mol to 450 g/mol, from150 g/mol to 400 g/mol or from 200 g/mol to 400 g/mol.

In some embodiments, the one or more active pharmaceutical compounds areselected from compounds having a log P of not greater than 5, forexample not greater than 4.5, not greater than 4, not greater than 3.5or not greater than 3, wherein P is the octanol-water partitioncoefficient determined at 25° C. (also denoted “Pow”).

As is well-understood by the skilled person, the partition coefficient Pis the ratio of concentrations of a compound between two specifiedsolvents (in this case, octanol and water), and log P is the logarithmof that ratio. Log P is therefore a measure of lipophilicity orhydrophobicity. A higher value of log P indicates a more lipophiliccompound.

In some embodiments, the one or more active pharmaceutical compounds areselected from compounds having a molecular weight of not greater than500 g/mol and a log P of not greater than 5, wherein P is theoctanol-water partition coefficient determined at 25° C.

In some embodiments, the one or more active pharmaceutical compounds areselected from compounds which are sparingly soluble, slightly soluble,very slightly soluble or practically insoluble as defined inSolubility—Part III—General Notices of British Pharmacopoeia (BP) 2019and European Pharmacopoeia (EP) 9th Edition and have one or more of alog P of not greater than 5, wherein P is the octanol-water partitioncoefficient determined at 25° C., and a molecular weight of not greaterthan 500 g/mol.

In some embodiments, the one or more active pharmaceutical compounds areselected from compounds which are sparingly soluble, slightly soluble,very slightly soluble or practically insoluble as defined inSolubility—Part III—General Notices of British Pharmacopoeia (BP) 2019and European Pharmacopoeia (EP) 9th Edition and have a log P of notgreater than 5, wherein P is the octanol-water partition coefficientdetermined at 25° C., and a molecular weight of not greater than 500g/mol.

Non-limiting examples of compounds which may be loaded onto the materialof the invention include cardiovascular drugs such as Felodipine,Telmisartan, Valsartan, Carvedilol, Nifedipine, Nimodipine andCaptopril; lipid-lowering drugs such as Lovastatin, Fenofibrate andEzetimibe; antiviral drugs such as Atazanavir and Ritonavir; analgesicssuch as Ibuprofen, Meloxicam, Ketoprofen, Aceclofenac, Celecoxib,Indomethacin, Phenylbutazone and Flurbiprofen; anti-fungal drugs such asItraconazole, Griseofulvin and Ketoconazole; antiepileptic drugs such asCarbamazepine, Oxcarbazepine and Rufinamide; anticancer drugs such asCamptothecin, Danazol and Paclitaxel; and other poorly soluble drugssuch as Glibenclamide, Cyclosporine, Cinnarizine, Furosemide andDiazepam. One or a combination of two or more of these compounds may beloaded onto the particulate material of the invention to improvesolubility and/or provide an extended or sustained release profile. Insome embodiments, the one or more active pharmaceutical compounds areselected from one or more of Furosemide, Ibuprofen and Felodipine.

Thus another aspect of the invention is a pharmaceutical compositioncomprising a particulate material according to the first aspect loadedwith one or more active pharmaceutical compounds. In some embodiments,the particulate material is surface-loaded with one or more activepharmaceutical compounds. In some embodiments, the one or more activepharmaceutical compounds are selected from one or more of the compoundslisted above.

In some embodiments, the pharmaceutical composition is anenhanced-solubility Felodipine composition comprising a particulatematerial according to the first aspect and Felodipine adsorbed onto thesurface of the particulate material. Some aspects of the inventionprovide the enhanced-solubility Felodipine composition for use intherapy. Some aspects of the invention provide the enhanced-solubilityFelodipine composition for use in the treatment of a disease or disorderselected from high blood pressure and stable angina. Some aspects of theinvention provide methods of treating a patient suffering from a diseaseor disorder selected from high blood pressure and stable angina,comprising administering to the patient a therapeutically acceptableamount of the enhanced-solubility Felodipine composition describedabove.

In some embodiments, the pharmaceutical composition is anenhanced-solubility Furosemide composition comprising a particulatematerial according to the first aspect and Furosemide adsorbed onto thesurface of the particulate material. Some aspects of the inventionprovide the enhanced-solubility Furosemide composition for use intherapy. Some aspects of the invention provide the enhanced-solubilityFurosemide composition for use in the treatment of a disease or disorderselected from oedema and hypertension. Some aspects of the inventionprovide methods of treating a patient suffering from a disease ordisorder selected from oedema and hypertension, comprising administeringto the patient a therapeutically acceptable amount of theenhanced-solubility Furosemide composition described above.

In some embodiments, the pharmaceutical composition is anenhanced-solubility Ibuprofen composition comprising a particulatematerial according to the first aspect and Ibuprofen adsorbed onto thesurface of the particulate material. Some aspects of the inventionprovide the enhanced-solubility Ibuprofen composition for use intherapy. Some aspects of the invention provide the enhanced-solubilityIbuprofen composition for use in the treatment of a disease or disorderselected from pain, fever and inflammation. Some aspects of theinvention provide methods of treating a patient suffering from a diseaseor disorder selected from pain, fever and inflammation, comprisingadministering to the patient a therapeutically acceptable amount of theenhanced-solubility Ibuprofen composition described above.

An aspect of the invention is a dosage form comprising thepharmaceutical composition of the second aspect. In some embodiments,the dosage form is an oral dosage form. In some embodiments, the dosageform is a tablet or capsule.

The dosage form may additionally comprise one or more pharmaceuticallyacceptable binders, carriers, diluents or excipients well-known to theskilled person.

Some aspects of the invention provide a pharmaceutical composition asdescribed above, for use in therapy. Some aspects of the inventionprovide the use of a pharmaceutical composition as described above inthe manufacture of a medicament. Some aspects of the invention provide amethod of treatment of the human or animal body, comprisingadministration of a therapeutically effective amount of a pharmaceuticalcomposition described above to a patient in need thereof. Other aspectsof the invention provide a method of treating the human or animal body,comprising administering to a patient in need thereof a therapeuticallyeffective amount of a pharmaceutical composition described above.

A wide range of diseases or disorders may be treated in these aspects,depending on the particular active pharmaceutical compound or compoundswhich are loaded onto the particulate material.

An aspect of the invention is a method of improving the solubility of anactive pharmaceutical compound, comprising loading the compound onto theparticulate material according to the first aspect. The activepharmaceutical compound may be one of the compounds mentioned above.

An aspect of the invention is the use of a particulate materialaccording to the first aspect as a solubility-enhancing carrier for oneor more active pharmaceutical compounds.

In some embodiments, apparent solubility is increased by a factor of atleast 1.1, for example at least 1.15, at least 1.2, at least 1.25 or atleast 1.3 through this method. In some cases, solubility is increased bya factor of up to around 10.

The present invention also relates to a means to provide an extendedrelease (or sustained release) composition of an active pharmaceuticalcompound. When the polymer solution also contains an activepharmaceutical compound, the compound becomes at least partiallyentrapped within the porous polymeric particles after spray-drying. Therelease of the compound from the particles is thereby limited andbecomes extended, or sustained, over a longer period of time.

Thus the invention also provides a method of manufacturing an extendedrelease pharmaceutical composition, comprising spray-drying a solutioncomprising polymer and one or more active pharmaceutical compounds toform a particulate material, the particulate material comprising porouspolymeric particles, the average pore diameter being from 2 to 50 nm,wherein the porous polymeric particles have a volume mean diameterD[4,3] of less than 100 μm.

SUMMARY OF THE FIGURES

So that the invention may be understood, and so that further aspects andfeatures thereof may be appreciated, embodiments illustrating theprinciples of the invention will now be discussed in further detail withreference to the accompanying figures, in which:

FIG. 1 shows SEM images of mesoporous cellulose acetate butyrateparticles according to the invention, prepared by a spray dryingprocess, including (a) a CAB particle cross-section at a magnificationof ×5000 and a scale bar of 1 μm and (b) the internal mesoporousstructure of a particle at a magnification of ×30,000 and a scale bar of100 nm.

FIG. 2 shows SEM images of mesoporous cellulose acetate butyrateparticles according to the invention, prepared by a spray dryingprocess, including (a) a CAB particle surface at a magnification of×5000 and a scale bar of 1 μm, and (b) a CAB particle surface at amagnification of ×33,000 and a scale bar of 100 nm.

FIG. 3 shows DSC thermograms of Felodipine raw material (solid line) andFelodipine-loaded mesoporous CAB particles (dashed line), under ascanning rate of 10° C./min and a scanning range of 50-250° C.

FIG. 4 shows DSC thermograms of Ibuprofen raw material (solid line) andIbuprofen-loaded mesoporous CAB particles (dashed line), under ascanning rate of 10° C./min and a scanning range of 40-250° C.

FIG. 5 shows DSC thermograms of Furosemide raw material (solid line) andFurosemide-loaded mesoporous CAB particles (dashed line), under ascanning rate of 10° C./min and a scanning range of 100-300° C.

FIG. 6 shows dissolution profiles of Felodipine raw material (solidline) and Felodipine-loaded mesoporous CAB particles (dashed line).Testing conditions: phosphate buffer pH 6.5+0.25% SLS, 500 mL, USPapparatus 1 (rotating basket), 50 rpm, HPLC method (mobile phase: pH 3phosphate buffer:acetonitrile:methanol (30:45:25); column: C18, 15cm×4.6 mm, 5 μm; flow rate: 1 mL/min; injection volume: 40 μL; detector:UV, 362 nm).

FIG. 7 shows dissolution profiles of Ibuprofen raw material (solid line)and Ibuprofen-loaded mesoporous CAB particles (dashed line). Testingconditions: HCL-NaCl medium pH 3+0.25% SLS, 900 mL, USP apparatus 1(rotating basket), 100 rpm, HPLC method (mobile phase: pH 3 phosphatebuffer:acetonitrile (60:40); column: C18, 15 cm×4.6 mm, 5 μm; flow rate:2 mL/min; injection volume: 20 μL; detector: UV, 254 nm).

FIG. 8 shows dissolution profiles of Furosemide raw material (solidline) and Furosemide-loaded mesoporous CAB particles (dashed line).Testing conditions: HCL-NaCl medium pH 3+0.25% SLS, 900 mL, USPapparatus 1 (rotating basket), 100 rpm, HPLC method (mobile phase: pH 3phosphate buffer:acetonitrile (60:40); column: C18, 15 cm×4.6 mm, 5 μm;flow rate: 1 mL/min; injection volume: 10 μL; detector: UV, 234 nm).

FIG. 9 shows dissolution profiles of Felodipine raw material (dottedline with triangular markers), spray-dried raw Felodipine (dotted linewith square markers) and Felodipine-loaded mesoporous CAB particlesprepared by co-spray drying a solution containing CAB and threedifferent levels of Felodipine: 5 wt %, 15 wt % and 25 wt % (solidlines). Testing conditions: phosphate buffer pH 6.5+0.25% SLS, 500 mL,USP apparatus 1 (rotating basket), 50 rpm, HPLC method (mobile phase: pH3 phosphate buffer:acetonitrile:methanol (30:45:25); column: C18, 15cm×4.6 mm, 5 μm; flow rate: 1 mL/min; injection volume: 40 μL; detector:UV, 362 nm).

FIG. 10 shows SEM images of mesoporous cellulose acetate butyrateparticles according to the invention, prepared by co-spray drying asolution of CAB and Felodipine, including (a) drug loading of 5 wt %,(b) drug loading of 10 wt % and (c) drug loading of 25 wt %. SEM imageswere taken at 30,000× magnification with a scale bar of 100 nm.

FIG. 11 shows CLSM images of mesoporous cellulose acetate butyrateparticles loaded with fluorescein by two different methods (a)post-loading with fluorescein, and (b) co-spray drying with fluorescein.

FIG. 12 shows plots of (a) cumulative distribution of pore volume ofparticles of Sample 8, and (b) the pore size distribution curve for theparticles of Sample 8 determined according to the BJH method.

EXAMPLES

Aspects and embodiments of the present invention will now be discussedin the following examples. Further aspects and embodiments will beapparent to those skilled in the art. All documents mentioned in thistext are incorporated herein by reference.

Characterisation of Particle Properties

In the Examples below, the pore size, pore volume and specific surfacearea of polymeric mesoporous particles were analysed by gas adsorptionporosimetry using pore size analyser Quantachrome Nova 4200e. Eachsample was degassed under vacuum at 100° C. for 24 h before obtainingnitrogen adsorption-desorption measurements.

Morphology of mesoporous particles was examined by scanning electronmicroscopy (SEM) in JEOL JSM-7800F operating at 1 kV under a highvacuum. The samples were not gold-coated to retain sample integrity,i.e. original surface features. Approximately 1 mg of each sample wasplaced onto a double-sided adhesive strip on a sample holder.

Particle size of samples was determined by laser diffraction usingparticle size analyser Sympatec HELOS/BR and dry disperser RODOS withfeeder VIBRI. The measuring range was 0-195 μm. Approximately 0.2 g ofeach sample was placed in the feeder tray. The time of each measurementwas 10 s with powder dispensing pressure of 300 kPa. The results wereobtained as volume mean diameter (VMD; D[4,3]) and given as the averageof three analyses for each sample.

To assess the level of drug loading of the particles, a known amount ofdrug-loaded mesoporous particles were dissolved in 25 ml of acetone anddiluted with a corresponding dissolution medium to 500 ml, thensonicated for 30 min.

The concentrations of dissolved drug were then determined using HPLC ina C18 column (15 cm×4.6 mm, 5 μm) and UV detector at 362 nm in anAgilent 1200 HPLC system.

Example 1—Preparation of Cellulosic Mesoporous Particles

4 g of cellulose acetate butyrate (CAB) or cellulose acetate (CA), orethyl cellulose (EC) were dissolved in 200 mL of either theacetone:water or ethyl acete:isopropanol mixtures prepared at a volumeratio of 90:10. The resulting polymer solutions were then spray driedwith a two-fluid nozzle. A mini spray dryer Buchi B-290 in closed modewith nitrogen in the Inert Loop Buchi B-295 (Flawil, Switzerland) wasused with a feed rate of 5 mL/min, nitrogen flow rate of 600 L/h,atomization pressure of 200 KPa, and a drying gas flow rate of 30 m³/h.The spray drying process was operated with an inlet temperature of 100°C. All materials and solvent were pharmaceutical grade.

Table 1 below shows the results of measurements taken on the particulatematerial produced in the spray drying.

TABLE 1 Average Surface pore Pore Particle area diameter volume sizePolymer Sample # Solvent mixture (cm²/g) (nm) (cm³/g) (μm) Mesoporous 1Acetone:water 12.8 16.3 0.05 48.8 ethyl cellulose (EC) Mesoporous 2Acetone:water 32.6 24.9 0.18 22.5 cellulose acetate butyrate (CAB)Mesoporous 3 Acetone:water 15.7 24.8 0.09 32.6 cellulose acetate (CA)Mesoporous 4 Ethyl  6.6 15.1 0.02 19.3 cellulose acetate:isopropanolacetate butyrate (CAB)

FIG. 1 shows SEM images of the particles of Sample 2. FIG. 1(a) is across-section of a broken particle showing the porous internal structureat a magnification of ×5000. FIG. 1(b) shows the same particlecross-section at a magnification of ×30,000, which shows the mesoporousinternal structure in greater detail.

FIG. 2 shows SEM images of the particles of Sample 2. FIG. 2(a) is theexternal surface of a particle showing the porous surface structure at amagnification of ×5000. FIG. 2(b) shows the same particle surface at amagnification of ×33,000, which shows the mesoporous surface structurein greater detail.

Example 2—Preparation of CAB Polymeric Mesoporous Particles

Polymeric mesoporous particles were manufactured from various types ofCAB having a butyryl content ranging from about 15% to about 60%, anacetyl content ranging from about 1% to about 30%, and a hydroxylcontent ranging from about 0.5% to about 5% (ex Eastman Chemical).Solvent mixtures of acetone:water were prepared at volume ratios of80:20, 85:15 and 90:10. 4 g of CAB were dissolved in 200 mL of solventmixtures. Polymer solutions were then spray dried with a two-fluidnozzle. A mini spray dryer Buchi B-290 in closed mode with nitrogen inthe Inert Loop Buchi B-295 (Flawil, Switzerland) was used with a feedrate of 5 mL/min, nitrogen flow rate of 600 L/h, atomization pressure of200 kPa, and drying gas flow rate of 30 m³/h. The spray drying processwas operated with inlet temperature in the range of 60-140° C. Allmaterials and solvents were pharmaceutical grade.

Table 2 below shows details of the various samples produced:

TABLE 2 Average Inlet Solvent ratio Surface pore Pore temp. (v/v) areadiameter volume Sample (° C.) (acetone:water) (cm²/g) (nm) (cm³/g) 5 6080:20 45.6 ± 2.1 24.9 ± 0.6 0.29 ± 0.01 6 100 80:20 42.5 ± 0.6 22.6 ±2.2 0.24 ± 0.04 7 140 80:20 42.8 ± 3.3 20.4 ± 0.7 0.22 ± 0.01 8 60 85:1556.7 ± 6.9 20.8 ± 2.3 0.32 ± 0.03 9 100 85:15 44.3 ± 1.3 22.0 ± 1.3 0.25± 0.02 10 140 85:15 38.6 ± 5.9 23.9 ± 0.6 0.23 ± 0.03 11 60 90:10 42.5 ±2.9 27.2 ± 0.1 0.29 ± 0.02 12 100 90:10 32.6 ± 1.0 24.1 ± 1.2 0.18 ±0.01 13 140 90:10 19.0 ± 3.6 27.0 ± 1.3 0.13 ± 0.01

Example 3—Preparation of Felodipine-Loaded Mesoporous Particles

Mesoporous CAB particles of Sample 8 in Table 2 were added to a solutionof Felodipine (FELO, complies with USP 36, purity >98%) in ethanol (10mg/mL) to form a suspension at an initial drug load of 15% (w/w). Thesuspension was gently stirred for 12 h, then spray-dried at inlettemperature of 100° C. using a mini spray dryer Buchi B-290 and inertloop Buchi B-295 in closed mode with nitrogen flow rate of 600 L/min,feed rate of 5 mL/min, and drying gas flow rate of 30 m³/h. Allmaterials and solvent were pharmaceutical grade.

Example 4—Preparation of Ibuprofen-Loaded Mesoporous Particles

Mesoporous CAB particles of Sample 8 in Table 2 were added to a solutionof Ibuprofen (IBU, purity >98%) in ethanol (10 mg/mL) to form asuspension at an initial drug load of 20% (w/w). The suspension wasgently stirred for 12 h, then spray-dried at inlet temperature of 80° C.using a mini spray dryer Buchi B-290 and inert loop Buchi B-295 underthe same process parameters as Example 3. All materials and solvent werepharmaceutical grade.

Example 5—Preparation of Furosemide-Loaded Mesoporous Particles

Mesoporous CAB particles of Sample 8 in Table 2 were added to a solutionof Furosemide (FURO, complies with USP 38, purity >99%) in ethanol (10mg/mL) to form a suspension at an initial drug load of 21% (w/w). Thesuspension was gently stirred for 12 h, then spray-dried using the sameapparatus and under the same process parameters as Example 3. Allmaterials and solvent were pharmaceutical grade.

Example 6—Co-Spray Dried Felodipine-CAB Polymeric Particles for ExtendedRelease

4.0 g of CAB was mixed with 0.2 g, 0.6 g and 1.0 g of Felodipine toproduce mixtures of polymer and drug with 5, 15 and 25% drug loading(w/w), respectively (i.e. drug loading in % w/w herein is calculated bydividing the mass of drug compound added to the solution by the mass ofpolymeric particles added to the solution, then multiplying by 100).These mixtures were then each dissolved in 200 mL of acetone:water atratio of 85:15 (v/v) and co-spray dried using a mini spray dryer BuchiB-290 in closed mode with nitrogen in the Inert Loop Buchi B-295(Flawil, Switzerland), inlet temperature of 100° C., nitrogen flow rateof 600 L/min, feed rate of 5 mL/min, and drying gas flow rate of 30m³/h. All materials and solvent were pharmaceutical grade.

Table 3 below sets out the properties of the co-spray driedFelodipine-CAB porous particles (n=3; mean±standard deviation).

TABLE 3 Average Felodipine Surface pore Sample loading area diameterPore volume # (% w/w) (cm²/g) (nm) (cm³/g) 14 5 46.3 ± 2.5 23.7 ± 0.60.28 ± 0.02 15 15 14.2 ± 3.4 17.2 ± 2.5 0.06 ± 0.01 16 25 10.4 ± 0.413.7 ± 1.4 0.04 ± 0.01

SEM images of the particles having different levels of drug loading areshown in FIG. 10.

Example 7—Thermal Analysis of Drug-Loaded Mesoporous Particles

Thermal properties of the drug-loaded mesoporous particles made inExamples 3-5 were characterised by DSC instrument TA Q 200. Samples wereaccurately weighed (approximately 3-5 mg) into Tzero aluminium pans andheated in the temperature range of 50-300° C. at a scanning rate of 10°C./min under nitrogen. TA universal analysis 2000 software (version 4.5)was employed to analyse the resulting DSC graphs.

FIGS. 3-5 show the DSC thermograms for each of Examples 3-5respectively, alongside the thermograms for the raw materials.

FIG. 3 shows DSC curves for Felodipine raw material (solid line) andFelodipine-loaded mesoporous particles (dotted line). A strongendothermic phase transition occurs at 146.3° C. for the raw material,which demonstrates its crystalline nature. No corresponding phasetransitions are evident for the Felodipine adsorbed onto the mesoporousparticles, showing that it is in amorphous form, which explains theenhanced solubility described below.

FIG. 4 shows DSC curves for Ibuprofen raw material (solid line) andIbuprofen-loaded mesoporous particles (dotted line). A strongendothermic phase transition occurs at 75.24° C. for the raw material,which demonstrates its crystalline nature. Only a very weakcorresponding phase transition is evident for the Ibuprofen adsorbedonto the mesoporous particles, showing that the majority of the materialis in amorphous form, which explains the enhanced solubility describedbelow.

FIG. 5 shows DSC curves for Furosemide raw material (solid line) andFurosemide-loaded mesoporous particles (dotted line). Phase transitionsoccur at around 220° C. and 265° C. for the raw material, whichdemonstrates its crystalline nature. No corresponding phase transitionsare evident for the Furosemide adsorbed onto the mesoporous particles,showing that it is in amorphous form, which explains the enhancedsolubility described below.

Example 8—Dissolution Profiles of FELO-Loaded Mesoporous Particles

Dissolution testing was performed using USP I apparatus (rotatingbasket, 50 rpm) in an Erweka DT 126 dissolution tester. Samples of thematerial as prepared in Example 3 containing 20 mg of FELO were loadedinto a HPMC hard-shell capsule and tested in 500 mL of USP pH 6.5 mediumwith 0.25% sodium lauryl sulfate (SLS) at 37° C. (adapted from USP 36monograph with a reduction of SLS concentration from 1.0 to 0.25%).Samples were withdrawn during a 120-min period at the followingtimepoints: 15, 30, 60, 90, and 120 min. The concentrations of dissolvedFELO were determined according to a HPLC method described in UnitedStates Pharmacopoeia (USP version 36) with mobile phase of USP pH 3phosphate buffer:acetonitrile:methanol (30:45:25), C18 column (15 cm×4.6mm, 5 μm), flow rate of 1 mL/min, injection volume of 40 μL, and UVdetector at 362 nm in an Agilent 1200 HPLC system.

The results are shown in FIG. 6 for the FELO-loaded particles of Example3 alongside the results for dissolution of the FELO raw material. As canbe clearly seen from the plot, the dissolution of Felodipine is greatlyenhanced by adsorbing the compound onto the mesoporous particulatematerial. After 120 mins the dissolution of Felodipine is 10× that seenafter the same period for the raw material (i.e. the compound notadsorbed onto any carrier). Indeed, all of the Felodipine adsorbed ontothe mesoporous particulate material is fully dissolved after 120 mins,compared with only around 10% of the raw material after the same timeperiod.

Example 9—Dissolution Profiles of IBU-Loaded Mesoporous Particles

Dissolution testing of IBU-loaded mesoporous particles as prepared inExample 4 was performed by using USP I apparatus (rotating basket, 100rpm) in an Erweka DT 126 dissolution tester. Samples containing 50 mg ofIBU were loaded into a HPMC hard-shell capsule and tested in 900 mL ofpH 3.0 medium with 0.25% SLS at 37° C. The pH 3 medium was prepared bydissolving 2 g of sodium chloride and 2.5 g of SLS in 400 mL ofdeionised water, then adding 0.1 mL of hydrochloric acid 37%, anddiluting with deionised water to 1000.0 mL. The concentrations ofdissolved IBU were determined using a HPLC method with mobile phase ofphosphate buffer pH 3: acetonitrile (60:40), C18 column (15 cm×4.6 mm, 5μm), flow rate of 2 mL/min, injection volume of 20 μL, and UV detectorat 254 nm in an Agilent 1200 HPLC system.

The results are shown in FIG. 7 for the IBU-loaded particles of Example4 alongside the results for dissolution of the IBU raw material. After120 mins, all of the Ibuprofen which was adsorbed onto the mesoporousparticulate material was dissolved, compared with only 73.4% for theIbuprofen raw material. Furthermore, a high dissolution rate (97.4%) isachieved for the adsorbed Ibuprofen after a relatively short period oftime (60 mins).

Example 10—Dissolution Profiles of FURO-Loaded Mesoporous Particles

Dissolution testing of FURO-loaded mesoporous particles as prepared inExample 5 was performed by using USP I apparatus (rotating basket, 100rpm) in an Erweka DT 126 dissolution tester. Samples containing 40 mgFURO were loaded into a HPMC hard-shell capsule and tested in 900 mL ofHCl—NaCl pH 3.0 medium with 0.25% SLS at 37° C. The concentrations ofdissolved FURO were determined using a HPLC method with mobile phase ofphosphate buffer pH 3: acetonitrile (60:40), C18 column (15 cm×4.6 mm, 5μm), column temperature of 35° C., flow rate of 1 mL/min, injectionvolume of 10 μL, and UV detector at 234 nm in an Agilent 1200 HPLCsystem.

The results are shown in FIG. 8 for the FURO-loaded particles of Example5 alongside the results for dissolution of the FURO raw material. Asignificantly higher dissolution rate (87.6%) is achieved for theFurosemide when adsorbed onto the mesoporous particulate material of theinvention, compared with only 65.3% for the Furosemide raw material,after 120 mins.

Example 11—Dissolution Profiles of Co-Spray Dried Felodipine-CABPolymeric Particles

Dissolution testing of the FELO-loaded mesoporous particles as preparedin Example 6 by the co-spray drying of polymer and Felodipine wasperformed by using USP I apparatus (rotating basket, 50 rpm) in anErweka DT 126 dissolution tester. Samples of the material as prepared inExample 6 containing 20 mg of FELO were loaded into a HPMC hard-shellcapsule and tested in 500 mL of USP pH 6.5 medium with 0.25% sodiumlauryl sulfate (SLS) at 37° C. (adapted from USP 36 monograph with areduction of SLS concentration from 1.0 to 0.25%). Samples werewithdrawn during a 10-hour period at the following timepoints: 0.5, 1,2, 6, and 10 hours. The concentrations of dissolved FELO were determinedaccording to a HPLC method described in United States Pharmacopoeia (USPversion 36) with mobile phase of USP pH 3 phosphatebuffer:acetonitrile:methanol (30:45:25), C18 column (15 cm×4.6 mm, 5μm), flow rate of 1 mL/min, injection volume of 40 μL, and UV detectorat 362 nm in an Agilent 1200 HPLC system.

The results are shown in FIG. 9. From the dissolution plots it isevident that both Felodipine raw material and spray-dried raw Felodipine(dotted lines) exhibit poor dissolution, as also evidenced in FIG. 6. Bycontrast, mesoporous polymeric particles produced by co-spray dryingsolutions of Felodipine and CAB show much higher dissolution rates aftera given period of time, across a range of drug loadings (5%, 15% and25%). Thus it is evident that the solubility of the compound is enhancedby its loading onto the mesoporous particles.

Additionally, a comparison of FIG. 9 with FIG. 6 reveals thatsustained-release properties are imparted on the Felodipine-loadedparticles of Example 6 (FIG. 9) relative to those of Example 3 (FIG. 6).When Felodipine is co-spray dried with the polymer, the drug is releasedmore slowly from the particles over an extended period. Morespecifically, for the 5%, 15% and 25% loaded particles, after 2 hoursaround 44%, 64% and 66% of the loaded Felodipine had dissolved,respectively, rising to 59%, 81% and 87% respectively after 10 hours.This compares with around 100% dissolution after 2 hours for thepost-loaded Felodipine-containing particles of Example 3 (FIG. 6).

Example 12—Confocal Laser Scanning Microscopy (CLSM) of MesoporousParticles Loaded with Fluorescein

CLSM was performed on some of the mesoporous particles loaded with amodel poorly-soluble compound, fluorescein, to demonstrate thedistribution of the model compound.

The mesoporous CAB particles of Sample 8 (Table 2) were post-loaded withfluorescein by following a procedure equivalent to that of Example 3,but substituting fluorescein for felodipine. Mesoporous CAB particles ofSample 8 in Table 2 were added to a solution of Fluorescein(Sigma-Aldrich, analytical reagent) in ethanol (2 mg/mL) to form asuspension at an initial drug load of 20% (w/w). The suspension wasgently stirred for 12 h, then spray-dried at inlet temperature of 100°C. using a mini spray dryer Buchi B-290 and inert loop Buchi B-295 inclosed mode with nitrogen flow rate of 600 L/min, feed rate of 5 mL/min,and drying gas flow rate of 30 m³/h. These particles post-loaded withfluorescein were denoted Sample 17.

Fluorescein-loaded mesoporous particles were also prepared by co-spraydrying. 4.0 g of CAB was mixed with 0.8 g of fluorescein. These mixtureswere then each dissolved in 200 mL of acetone:water at ratio of 85:15(v/v) and co-spray dried using a mini spray dryer Buchi B-290 in closedmode with nitrogen in the Inert Loop Buchi B-295 (Flawil, Switzerland),inlet temperature of 100° C., nitrogen flow rate of 600 L/min, feed rateof 5 mL/min, and drying gas flow rate of 30 m³/h. The spray-driedparticles were denoted Sample 18.

The distribution of fluorescein in Samples 17 and 18 was qualitativelyevaluated by using Leica confocal microscope TCS SP5 II (Wetzlar,Germany) with 10× and 20× dry objective lens. Excitation and emissionwavelength for fluorescein samples were 488 and 525 nm, respectively.Confocal images of fluorescein samples were obtained at 515-535 nm.Scanning depth was 2 μm for both samples with scanning speed was 200 Hz.

Images obtained from the CLSM are shown in FIG. 11. FIG. 11(a) shows aparticle of Sample 17 and FIG. 11(b) shows a particle of Sample 18. TheCLSM image of Sample 18 shows that co-spray drying with the poorlysoluble compound leads to a distribution of the compound both entrappedwithin the particles and adsorbed at the particle surface. By contrast,post-loading of particles leads to deposition of the poorly solublecompounds only within the surface pores and the total drug loading islower.

Example 13—Determination of Pore Size Distribution

The pore volume and pore size distribution of polymeric mesoporousparticles of Sample 8 were analysed by gas adsorption porosimetry usingpore size analyser Quantachrome Nova 4200e under the BJH theoryaccording to the method set out in ISO 15901-2 of 2006. Each sample wasdegassed under vacuum at 100° C. for 24 h before obtaining nitrogenadsorption-desorption measurements.

The results are set out in Table 4 below:

TABLE 4 dV/dD Cumulative Pore Cumulative Pore Pore Diameter, [(cm³/nm/g)× Volume, V_(cum) Volume Fraction D (nm) 10⁻³] (cm³/g) (%) 0.0000 0.000.0000 0.0% 1.1960 0.961 0.0002 0.1% 1.3222 5.08 0.0005 0.2% 1.4339 6.550.0016 0.5% 1.5494 7.79 0.0021 0.7% 1.7745 6.65 0.0046 1.6% 2.0238 6.750.0054 1.9% 2.2210 6.06 0.0071 2.4% 2.4822 4.79 0.0083 2.8% 2.7720 4.390.0097 3.3% 3.0842 3.15 0.0106 3.7% 3.4220 3.01 0.0118 4.1% 3.8656 3.390.0135 4.6% 4.3895 2.01 0.0146 5.0% 4.9998 2.33 0.0162 5.6% 5.7476 1.900.0177 6.1% 6.5752 2.45 0.0198 6.8% 8.0070 2.49 0.0248 8.5% 9.8003 3.130.0297 10.2% 11.2361 3.29 0.0340 11.7% 12.5497 4.05 0.0393 13.5% 14.37624.49 0.0499 17.1% 16.8172 5.60 0.0641 22.0% 19.7873 5.18 0.0817 28.0%22.8421 5.08 0.0954 32.8% 25.5916 5.52 0.1108 38.0% 29.0798 5.57 0.134246.0% 33.9831 4.14 0.1574 54.0% 40.2092 4.76 0.1900 65.2% 50.0931 3.080.2298 78.9% 65.6605 2.18 0.2694 92.5% 91.9799 0.636 0.2913 100.0%

The cumulative distribution of pore volume is plotted in FIG. 12a . Thepore size distribution, presented graphically as a plot of dV/dD versuspore size, is shown in FIG. 12 b.

The features disclosed in the foregoing description, or in the followingclaims, or in the accompanying drawings, expressed in their specificforms or in terms of a means for performing the disclosed function, or amethod or process for obtaining the disclosed results, as appropriate,may, separately, or in any combination of such features, be utilised forrealising the invention in diverse forms thereof.

While the invention has been described in conjunction with the exemplaryembodiments described above, many equivalent modifications andvariations will be apparent to those skilled in the art when given thisdisclosure. Accordingly, the exemplary embodiments of the invention setforth above are considered to be illustrative and not limiting. Variouschanges to the described embodiments may be made without departing fromthe spirit and scope of the invention.

For the avoidance of any doubt, any theoretical explanations providedherein are provided for the purposes of improving the understanding of areader. The inventors do not wish to be bound by any of thesetheoretical explanations.

Any section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

Throughout this specification, including the claims which follow, unlessthe context requires otherwise, the words “have”, “comprise”, and“include”, and variations such as “having”, “comprises”, “comprising”,and “including” will be understood to imply the inclusion of a statedinteger or step or group of integers or steps but not the exclusion ofany other integer or step or group of integers or steps.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the context clearly dictates otherwise. Ranges may be expressedherein as from “about” one particular value, and/or to “about” anotherparticular value. When such a range is expressed, another embodimentincludes from the one particular value and/or to the other particularvalue. Similarly, when values are expressed as approximations, by theuse of the antecedent “about,” it will be understood that the particularvalue forms another embodiment. The term “about” in relation to anumerical value is optional and means, for example, +/−10%.

The words “preferred” and “preferably” are used herein refer toembodiments of the invention that may provide certain benefits undersome circumstances. It is to be appreciated, however, that otherembodiments may also be preferred under the same or differentcircumstances. The recitation of one or more preferred embodimentstherefore does not mean or imply that other embodiments are not useful,and is not intended to exclude other embodiments from the scope of thedisclosure, or from the scope of the claims.

1. A particulate material comprising porous polymeric particles, theaverage pore diameter being from 2 to 50 nm, wherein the porouspolymeric particles have a volume mean particle diameter D[4,3] of lessthan 100 μm and the material is obtained or obtainable by spray-drying apolymer solution.
 2. The particulate material according to claim 1,wherein the volume mean particle diameter D[4,3] of the particles isless than 50 μm.
 3. The particulate material according to claim 1,wherein the volume of pores in the material is greater than 0.10 cm³/g.4. The particulate material according to claim 1, wherein the surfacearea of the material is greater than 10 m²/g.
 5. The particulatematerial according to claim 1, wherein the average pore diameter is from10 to 30 nm.
 6. The particulate material according to claim 1, whereinthe particles comprise cellulosic polymer and the polymer solution is asolution comprising the same cellulosic polymer.
 7. The particulatematerial according to claim 6, wherein the cellulosic polymer isselected from one or more of cellulose esters and cellulose ethers. 8.The particulate material according to claim 6, wherein the cellulosicpolymer is selected from one or more of cellulose acetate butyrate,cellulose acetate, methyl cellulose, ethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose andhydroxypropyl methyl cellulose.
 9. The particulate material according toclaim 8, wherein the cellulosic polymer is cellulose acetate butyrate.10. The particulate material according to claim 1, wherein the inlettemperature during spray-drying of the polymer solution is lower thanthe glass transition temperature T_(g) of the polymer in the polymersolution.
 11. The particulate material according to claim 1, wherein theglass transition temperature T_(g) of the polymer in the polymersolution is greater than 100° C.
 12. The particulate material accordingto claim 1, wherein the solution comprises a solvent mixture comprisingwater and acetone.
 13. A pharmaceutical composition comprising aparticulate material according to claim 1 loaded with one or more activepharmaceutical compounds.
 14. (canceled)
 15. A method of treatment ofthe human or animal body, comprising administration of a therapeuticallyeffective amount of the pharmaceutical composition according to claim13.
 16. A method of manufacturing a particulate material comprisingspray-drying a polymer solution, the particulate material comprisingporous polymeric particles, the average pore diameter being from 2 to 50nm, wherein the porous polymeric particles have a volume mean diameterD[4,3] of less than 100 μm.
 17. The method according to claim 16,wherein the polymer solution is a solution comprising cellulosicpolymer.
 18. The method according to claim 17, wherein the cellulosicpolymer is selected from one or more of cellulose esters and celluloseethers.
 19. The method according to claim 17, wherein the cellulosicpolymer is selected from one or more of cellulose acetate butyrate,cellulose acetate, methyl cellulose, ethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose andhydroxypropyl methyl cellulose.
 20. The method according to claim 19,wherein the cellulosic polymer is cellulose acetate butyrate.
 21. Themethod according to claim 16, wherein the inlet temperature duringspray-drying of the polymer solution is lower than the glass transitiontemperature T_(g) of the polymer in the polymer solution.
 22. The methodaccording to claim 16, wherein the glass transition temperature T_(g) ofthe polymer in the polymer solution is greater than 100° C.
 23. Themethod according to claim 16, wherein the solution comprises a solventmixture comprising water and acetone.
 24. The method according to claim16, wherein the solution comprises one or more active pharmaceuticalcompounds.
 25. The method according to claim 16, wherein thespray-drying is carried out in a spray-dryer under closed-mode withnitrogen, an inlet temperature of from 60 to 180° C. and an atomisationpressure of from 100 to 500 KPa.
 26. Use of a particulate materialaccording to claim 1 as a solubility-enhancing carrier for one or moreactive pharmaceutical compounds.